Office of Technology Development (OTD)

Michael Dwinell, PhD

Cellular metastasis is the most detrimental step in carcinoma disease progression, yet the mechanisms that regulate this process are poorly understood. CXCL12 and its receptor CXCR4 are chemokines that are co-expressed in several tissues and cell types throughout the body and play essential roles in development. CXCL12 has a wide range of effects on CXCR4 expressing cells including the directed migration of leukocytes, lymphocytes and hematopoietic stem cells. This signaling axis has also been described as an important regulator of directed carcinoma cell metastasis.

The present invention provides a method for treating and diagnosing metastatic tumors in patients. Endogenous CXCL12 expression in cells is silenced when its gene promoter becomes hypermethylated, promoting the increased metastasis of cancer cells. Detection of hypermethylation in these gene promoters can serve as biomarkers for both diagnosis and monitoring disease progression. The hypermethylation may be due to the activity of the DNA methyltransferase family of enzymes, specifically Dnmt1 and Dnmt3b. By inhibiting Dnmt1 and Dmnt3b with a methylase inhibitor or by genetic ablation of both enzymes, CXCL12 expression can be restored. Re-expression of functional, endogenous CXCL12 in colorectal carcinoma cells dramatically reduces metastatic tumor formation in mice as well as foci formation in soft agar.

• Method of diagnosing and monitoring metastatic tumors by detecting hypermethylation of the CXCL12 gene 
• Method of treating cancer by administering a therapeutic amount of CXCL12 
• Method of treating cancer through tumor re-expression of endogenous CXCL12 using gene therapy

In vitro cells assays and In vivo animal studies using SCID mouse model